Phenylpyrimidine amines as IgE inhibitors

ABSTRACT

An amine, which is substituted by phenyl-substituted pyrimidin; and phenyl; and a third substituent and its use as an immunoglobulin E (IgE) inhibitor.

The present invention relates to organic compounds, e.g. substitutedamines having pharmaceutical e.g. IgE-synthesis inhibiting, activity.

In one aspect the present invention provides a compound of formula

wherein

R₁ is halogen or halo(C₁₋₄)alkyl,

R₂ is hydrogen, halogen or halo(C₁₋₄)alkyl,

R₃ is halogen or halo(C₁₋₄)alkyl,

R₄ is hydrogen, (C₁₋₈)alkyl, hydroxy(C₁₋₆)alkyl or a group of formula

-   -   —CO—R₅,    -   —CO—(CH₂)_(m)—OR₆,    -   —CO—CO—R₇,    -   —CO—CO—OR₈,    -   —CO—N(R₉R₁₀),    -   —CO—(CH₂)_(n)—CO—R₁₁,    -   —CO—(CHR₁₅)—O—(CH₂)₀—CO—R₁₁,    -   —CO—(CH₂)_(p)—O—(CH₂)_(q)—O—(CH₂)_(r)—R₁₆,    -   —CO—O—(CH₂)_(s)—O—CO—R₁₇,    -   —CO—O—(CH₂)_(r)—N(R₁₈R₁₉),    -   —CO—O—(CH₂)_(u)NH—CO—CH(NH₂)—R₂₀, or    -   —CO—O—(CH₂)_(w)—NH—CO—R₁₇, wherein        -   R₅ is hydrogen, (C₁₋₈)alkyl, (C₃₋₈)cycloalkyl, amino,            (C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, aryl or heterocyclyl            which is a 5 or 6-membered heterocyclic ring system having 1            to 4 heteroatoms selected from N, O or S,        -   R₆ is hydrogen, (C₁₋₄)alkyl, (C₃₋₈)cycloalkyl, aryl,            (C₁₋₄)alkyl substituted by heterocyclyl which is a 5 or            6-membered heterocyclic ring system having 1 to 4            heteroatoms selected from N, O or S, amino(C₁₋₆)alkyl,            (C₁₋₄)alkylamino(C₁₋₆)alkyl, di(C₁₋₄)alkylamino(C₁₋₆)alkyl,            hydroxy(C₁₋₆)alkyl, hydroxy(C₁₋₄)alkylamino(C₁₋₆)alkyl or an            amino acid residue, e.g. —CH₂—CH(NH₂)—COOH,        -   R₇ and R₈ independently of each other are (C₁₋₄)alkyl,            (C₃₋₈)cycloalkyl, aryl or heterocyclyl which is a 5 or            6-membered heterocyclic ring system having 1 to 4            heteroatoms selected from N, O or S,        -   R₉ and R₁₀ independently of each other are hydrogen or            (C₁₋₄)alkyl or one of R₉ and R₁₀ is hydrogen and the other            is (C₃₋₈)cycloalkyl, (C₁₋₄)alkyl, aryl or heterocyclyl,        -   R₁₁ is (C₁₋₄)alkyl, —OR₁₂, —NR₁₃R₁₄, an amino acid, an            (C₁₋₄)alkylester thereof or a di(C₁₋₄)alkylester thereof,            -   R₁₂ is hydrogen or (C₁₋₄)alkyl,            -   R₁₃ and R₁₄ independently of each other are hydrogen,                (C₁₋₄)alkyl, amino(C₁₋₆)alkyl,                (C₁₋₄)alkylamino(C₁₋₆)alkyl,                di(C₁₋₄)alkylamino(C₁-)alkyl,        -   R₁₅ is hydrogen or (C₁₋₄)alkyl,        -   R₁₆ is hydrogen, (C₁₋₄)alkyl, carboxyl or carboxylic ester,        -   R₁₇ is amino(C₁₋₄)alkyl, (C₁₋₄)alkylamino(C₁₋₄)alkyl or            di(C₁₋₄)alkylamino(C₁₋₄)alkyl,        -   R₁₈ is hydrogen or (C₁₋₄)alkyl,        -   R₁₉ is hydroxy(C₁₋₄)alkyl,        -   R₂₀ is (C₁₋₄)alkyl or hydroxy(C₁₋₄)alkyl,        -   m is 0 to 4,        -   n is 2 to 8,        -   o is 0 to 4,        -   p is 0 to 4,        -   q is 1 to 8,        -   r is 0 to 4,        -   s is 1 to 4,        -   t is 1 to 4,        -   u is 1 to 6 and        -   w is 1 to 6.

In another aspect the present invention provides a compound of formula1, wherein

-   -   R₁ is chloro or trifluoromethyl,    -   R₂ is hydrogen or trifluoromethyl,    -   R₃ is chloro, fluoro or trifluoromethyl,    -   R₄ is hydrogen, (C₁₋₄)alkyl, e.g. methyl, hydroxy(C₁₋₄)alkyl,        e.g. hydroxyethyl, or a group of formula        -   —CO—R₅,        -   —CO—(CH₂)_(m)—OR₆,        -   —CO—CO—R₇,        -   —CO—CO—OR₈,        -   —CO—N(R₉R₁₀),        -   —CO—(CH₂)_(n)—CO—R₁₁,        -   —CO—(CHR₁₅)—O—(CH₂)_(o)—CO—R₁₁,        -   —CO—(CH₂)_(p)—O—(CH₂)_(q)—O—(CH₂)_(r)—R₁₆,        -   —CO—O—(CH₂)_(s)—O—CO—R₁₇,        -   —CO—O—(CH₂)_(r)—N(R₁₈R₁₉),        -   —CO—O—(CH₂)_(u)—NH—CO—CH(NH₂)—R₂₀, or        -   —CO—O—(CH₂)_(w)—NH—CO—R₁₇, wherein            -   R₅ is hydrogen, (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl,                dimethylamino, phenyl or heterocyclyl which is a                6-membered heterocyclic ring system having one O as a                heteroatom, e.g. tetrahydropyranyl,            -   R₆ is hydrogen, (C₁₋₄)alkyl, (C₁₋₂)alkyl substituted by                heterocyclyl which is a 5 or 6-membered heterocyclic                ring system having 1 or 2 heteroatoms selected from N or                O, e.g. including unsubstituted pyrrolidine, morpholine                and piperazine and piperazine substituted by e.g.                (C₁₋₂)alkyl or (C₁₋₂)hydroxyalkyl; amino(C₁₋₄)alkyl,                (C₁₋₂)alkylamino(C₁₋₄)alkyl,                di(C₁₋₂)alkylamino(C₁₋₄)alkyl, hydroxy(C₁₋₃)alkyl,                hydroxy(C₁₋₂)alkylamino(C₁₋₂)alkyl or an amino acid                residue, e.g. —CH₂—CH(NH₂)—COOH,            -   R₇ and R₈ independently of each other are (C₁₋₂)alkyl or                phenyl,            -   R₉ and R₁₀ independently of each other are hydrogen or                (C₁₋₂)alkyl,            -   R₁₁ is (C₁₋₂)alkyl, —OR₁₂, —NR₁₃R₁₄, an amino acid, an                (C₁₋₂)alkylester thereof or an di(C₁₋₂)alkylester                thereof, preferably an amino acid selected from the                group consisting of alanine, phenylalanine, glutamic                acid and lysine, wherein the binding is effected via the                α-amino group or in the case of e.g. lysine via the                ε-amino group,                -   R₁₂ is hydrogen or (C₁₋₂)alkyl,                -   R₁₃ and R₁₄ independently of each other are                    hydrogen, (C₁₋₂)alkyl, amino(C₁₋₄)alkyl,                    (C₁₋₂)alkylamino(C₁₋₄)alkyl,                    di(C₁₋₂)alkylamino(C₁₋₄)alkyl,            -   R₁₅ is hydrogen or (C₁₋₂)alkyl,            -   R₁₆ is hydrogen, (C₁₋₂)alkyl, carboxyl or carboxylic                ester,            -   R₁₇ is amino(C₁₋₂)alkyl,            -   R₁₈ is hydrogen or (C₁₋₂)alkyl,            -   R₁₉ is hydroxy(C₁₋₂)alkyl,            -   R₂₀ is (C₁₋₂)alkyl or hydroxy(C₁₋₂)alkyl,            -   m is 0 or 1,            -   n is2to 4,            -   o is 0 or 1,            -   p is 0 to 2,            -   q is 2 to 5,            -   r is 0 to 2,            -   s is 2,            -   t is 2,            -   u is 1 to 3 and            -   w is 1 to 3.

In another aspect the present invention provides a compound of formulaI, selected from the group consisting of

N-[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-N-(4-chloro-3trifluoromethyl-phenyl)-amine,

N-[4-(3-Trifluoromethyl-phenyl)-pyrimidin-2-yl]-N-(4-fluoro-3-trifluoromethyl-phenyl)-amine,

N-[4-(3-Trifluoromethyl-phenyl)-pyrimidin-2-yl]-N-(4-chloro-3-trifluoromethyl-phenyl)-amine,

N-[4-(3-Trifluoromethyl-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-amine,and

N-[4-(3Chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-amine,

wherein the amine group is further substituted by R₄, wherein R₄ is asdefined above.

In a further aspect the present invention provides a compound of formulaI wherein

-   -   R₁ is chloro,    -   R₂ is hydrogen,    -   R₃ is trifluoromethyl and    -   R₄ is hydrogen.

In a further aspect the present invention provides a compound of formulaI wherein

-   -   R₁ is chloro,    -   R₂ is hydrogen,    -   R₃ is trifluoromethyl and    -   R₄ is a group of formula —CO—O—(CH₂)_(z)—N[(C₂H₅OH)(CH₃)].

If not otherwise defined herein aryl includes phenyl. Halogen includesfluoro, chloro, bromo. Haloalkyl includes halo(C₁₋₄)alkyl, wherein halois one or more halogen, preferably trifluoromethyl. (C₃₋₈)cycloalkylincludes e.g. (C₃₋₆)cycloalkyl. Amino includes amino, (C₁₋₄)alkylaminoand di(C₁₋₄)alkylamino. Aminoalkyl includes amino(C₁₋₆)alkyl, e.g.(C₁₋₄)alkylamino(C₁₋₆)alkyl, di(C₁₋₄)alkylamino(C₁₋₆)alkyl, preferablydisubstituted amino(C₁₋₄)₄)alkylamino(C₁₋₄)alkyl, e.g. dimethyl- ordiethylamino(C₁₋₄)alkyl. Hydroxyalkylamino includes hydroxy(C₁₋₆)alkyl,hydroxy(C₁₋₄)alkylamino(C₁₋₆)alkyl, preferably hydroxy(C₁₋₃)alkyl orhydroxy(C₁₋₂)alkylamino(C₁₋₂)alkyl. Amino acid includes all natural andsynthetic amino acids, preferably α-amino acids, e.g. alanine,phenylalanine, glycine, glutamic acid and lysine. Amino acid includesone or more of amino acid, e.g. di- or tripeptides. Heterocyclylincludes 5 or 6 membered heterocyclic ring systems having 1 to 4heteroatoms selected from N, O or S. Preferably the heterocyclyl is a 5or 6 membered ring system having 1 or 2 heteroatoms selected from N orO. Preferred is pyrrolidine, morpholine and piperazine.

Any group may be unsubstituted or substituted, e.g. substituted bygroups as conventional in organic chemistry, e.g. including groupsselected from halogen, haloalkyl, alkylcarbonyloxy, alkoxy, hydroxy,amino, alkylcarbonylamino, aminoalkylcarbonylamino, hydroxyalkylamino,aminoalkylamino, alkylamino, dialkylamino, heterocyclyl having 5 or 6ring members and 1 to 4 heteroatoms selected from N,O,S;(C₁₋₄)alkylheterocyclyl, wherein heterocyclyl having 5 or 6 ring membersand 1 to 4 heteroatoms selected from N,O,S;hydroxy(C₁₋₄)alkylheterocyclyl, wherein heterocyclyl having 5 or 6 ringmembers and 1 to 4 heteroatoms selected from N,O,S; carboxyl,(C₁₋₄)alkylcarbonyloxy, amino(C₁₋₄)-alkylcarbonyloxy.

Compounds provided by the present invention are hereinafter designatedas “compound(s) of the present invention”. A compound of the presentinvention includes a compound in any form, e.g. in free form, in theform of a salt, in the form of a solvate and in the form of a salt and asolvate.

A salt of a compound of the present invention includes apharmaceutically acceptable salt, e.g. including a metal salt or an acidaddition salt. Metal salts include for example alkali or earth alkalisalts; acid addition salts include salts of a compound of formula I withan acid, e.g. including inorganic and organic acids, e.g. includingpharmaceutically acceptable acids, such as hydrochloric acid, sulfuricacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, tartaric acid.

A compound of the present invention in free form may be converted into acorresponding compound in the form of a salt; and vice versa. A compoundof the present invention in free form or in the form of a salt and inthe form of a solvate may be converted into a corresponding compound infree form or in the form of a salt in unsolvated form; and vice versa.

A compound of the present invention may exist in the form of isomers andmixtures thereof; e.g. optical isomers, diastereoisomers, cis-transconformers. A compound of the present invention may e.g. containasymmetric carbon atoms and may thus exist in the form of enantiomeres,diastereolsomeres and mixtures thereof, e.g. racemates. E.g. asubstitutent attached to an asymmetric carbon atom in a compound of thepresent invention may be in the R— or in the S-configuration, includingmixtures thereof. The present invention includes a compound of thepresent invention in any isomeric form and in any isomeric mixture.

Any compound described herein, e.g. a compound of the present invention,may be prepared as appropriate, e.g. according to a method asconventional, e.g. or as described herein.

A compound of the present invention wherein the amine group issubstituted by phenyl-substituted pyrimidin; and phenyl; and hydrogenmay be prepared e.g. according, e.g. analogously, to a method asconventional, preferably according to the following reaction scheme 1:

e.g. wherein in a compound of formula I, II and III R₁, R₂ and R₃ are asdefined above, and R₄ is H; and optionally further reacting a compoundobtained with an appropriate reagent to obtain a compound of of thepresent invention, e.g. a compound of formula I, wherein R₄ is asdefined above, but other than hydrogen; e.g. reacting a compound offormula I wherein R₄ is H and the other substituents are as definedabove

-   -   with an alkyliodide in the presence of NaH, to obtain a compound        of formula I wherein R₄ is alkyl,    -   with a bromo-hydroxyalkane to obtain a compound of formula I        wherein R₄ is hydroxyalkyl,    -   with a halogenide or an anhydride of a carboxylic acid of        formula R₅COOH wherein R₅ is as defined above, to obtain a        compound of formula I wherein R₄ is a group —CO—R₅, wherein R₅        is as defined above,    -   with phosgene to obtain a compound of formula I wherein R₄ is        —COCl and further reacting a compound obtained with a compound        of formula    -   a) R₆—(CH₂)_(m)—OH, wherein R₆ is as defined above and m is 0 to        obtain a compound of formula I wherein R₄ is a group of formula        —CO—(CH₂)_(m)—OR₆, wherein R₆ is as defined above and m is 0,    -   b) R₁₇—CO—O—(CH₂)_(s)—OH, wherein R₁₇ and s are as defined above        to obtain a compound of formula I wherein R₄ is a group of        formula —CO—O—(CH₂)_(s)—O—CO—R₁₇, wherein R₁₇ and s are as        defined above,    -   c) N(R₁₈R₁₉)—(CH₂)_(r)—OH, wherein R₁₈, R₁₉ and t are as defined        above to obtain a compound of formula I wherein R₄ is a group of        formula —CO—O—(CH₂)_(r)N(R₁₈R₁₉), wherein R₁₈, R₁₉ and t are as        defined above,    -   d) R₂₀—(NH₂)CH—CO—NH—(CH₂)_(u)—OH, wherein R₂₀ and u are as        defined above to obtain a compound of formula I wherein R₄ is a        group of formula —CO—O—(CH₂)_(u)—NH—CO—CH(NH₂)—R₂₀, wherein R₂₀        and u are as defined above,    -   e) R₁₇—CO—NH—(CH₂)_(w)—OH, wherein R₁₇ and w are as defined        above to obtain a compound of formula I wherein R₄ is a group of        formula —O—O—(CH₂)_(w)—NH—CO—R₁₇, wherein R₁₇ and w are as        defined above,    -   with a compound of formula R₅—CO—Cl, wherein R₅ is as defined        above to obtain a compound of formula I wherein R₄ is a group of        formula —CO—R₅, wherein R₅ is as defined above,    -   with a compound of formula R₆—O—(CH₂)_(m)—CO—Cl, wherein R₆ is        as defined above to obtain a compound of formula I wherein R₄ is        a group of formula —CO—(CH₂)_(m)—OR₆, wherein R₆ is as defined        above,    -   with a compound of formula R₇CO—CO—Cl, wherein R₇ is as defined        above to obtain a compound of formula I wherein R₄ is a group of        formula —CO—CO—R₇, wherein R₇ is as defined above,    -   with a compound of formula R₈—O—CO—CO—Cl, wherein R₈ is as        defined above, to obtain a compound of formula I wherein R₄ is a        group of formula —CO—CO—OR₈, wherein R₈ is as defined above,    -   with a compound of formula (R₉R₁₀)N—CO—Cl, wherein R₉ and R₁₀        are as defined above, to obtain a compound of formula I wherein        R₄ is a group of formula —CO—N(R₉R₁₀), wherein R₉ and R₁₀ are as        defined above,    -   with a compound of formula R₁₁—CO—(CH₂)_(n)—CO—Cl, wherein R₁₁,        and n are as defined above to obtain a compound of formula I        wherein R₄ is a group of formula —CO—(CH₂)_(n)—CO—R₁₁, wherein        R₁₁ and n are as defined above,    -   with a compound of formula R₁₁—CO—(CH₂)_(o)—O—(CHR₁₆)—CO—Cl,        wherein R₁₁, R₁₆ and o are as defined above to obtain a compound        of formula I wherein R₄ is a group of formula        —CO—(CHR₁₆)—O—(CH₂)_(o)—CO—R₁₁, wherein R₁₁, R₁₆ and o are as        defined above,    -   with a compound of formula R₁₆—(CH₂)_(r)—O—(CH₂)_(q)—O—(CH₂)_(p)        —CO—Cl, wherein R₁₆, r, q and p are as defined above to obtain a        compound of formula I wherein R₄ is a group of formula        —CO—(CH₂)_(p)—O—CH₂)_(q)—O—(CH₂)_(r)—R₁₆, wherein R₁₆, r, q and        p are as defined above,    -   with a compound of formula Cl—OC—(CH₂)_(y)—CO—Cl to obtain a        compound of formula I wherein R₄ is a group of formula        —CO—(CH₂)_(v)—CO—Cl and further reacting a compound obtained        with an amino acid, an amino acid mono(C₁₋₆)alkyl ester, an        amino acid di(C₁₋₆)alkyl ester or with a primary or secondary        amine, optionally containing additional amine groups to obtain a        compound of formula I wherein R₄ is a group of formula        —CO—(CH₂)_(v)—CO-amino acid, —CO—(CH₂)_(v)—CO— amino acid        mono(C₁₋₆)alkyl ester or —CO—(CH₂)_(v)—CO-amino acid        di(C₁₋₆)alkyl ester and v is 1 to 6, preferably 1 to 5.

Reactions of a compound of formula I wherein R₄ is H and the othersubstituents are as defined above with appropriate reagents to obtain acompound of formula I; wherein R₄ is as defined above, but other thanhydrogen, are alkylation or acylation reactions and may be carried outas appropriate, e.g. according, such as analogously, to a method asconventional, e.g. or as described above. In such reactionssubstituents, e.g. hydroxy or amine groups, may be protected beforereaction and deprotected during or after reaction.

In another aspect the present invention provides a process for theproduction of a compound of formula I comprising reacting a compound offormula II wherein R₁ is as defined above and ALK denotes alkyl orcycloalkyl, with a compound of formula III, wherein R₂ and R₃ are asdefined above, to obtain a compound of formula I wherein R₁, R₂ and R₃are as defined above, and R₄ is hydrogen, and optionally alkylating oracylating a compound obtained, e.g. and deprotecting groups if desired,to obtain a compound of formula I wherein R₁, R₂ and R₃ are as definedabove and R₄ is as defined above, but other than hydrogen, and isolatinga compound of formula I obtained from the reaction mixture.

Any compound described herein, e.g. a compound of the present invention,may be prepared as appropriate, e.g. according to a method asconventional, e.g. or as described herein. Compounds of formula II andof formula III are known or may be obtained e.g. according to a methodas conventional or as described herein.

The compounds of the present invention exhibit in vitro and in vivopharmacological activity and are therefore useful as pharmaceuticals:

In the course of an allergic response e.g. in the airways, T-helper type2 cells (Th2 cells) are generated from naïve T-cell precursors followingstimulation by allergen presented by dendritic cells (DC) in thepresence of the Th2 cytokine IL4. These Th2 cells induce a complexinflammatory response in the lung leading to the onset and progressionof allergic asthma. Cytokines produced by these Th2 cells, which includee.g. IL4, IL-5, IL-10 and IL-13, mediate the expansion ofpro-inflammatory effector cells such as eosinophils, basophils and mastcells which accumulate in the lungs.

In addition, IL4 and IL-13 induce IgE production by B-cells. Binding ofIgE to high affinity IgE receptors (FcεRl) on mast cells and basophilsresults, following crosslinking by allergen, in the activation of thepro-inflammatory cells and the release of mediators of allergicinflammation.

Based on these observations, it is expected that inhibition of both Th2cell mediated allergic inflammatory responses and effects on IgEproduction would provide a novel way to efficiently intervene inallergic asthma and other allergic diseases such as e.g. atopicdermatitis, allergic conjunctivitis and allergic rhinitis.

We have found that the compounds of the present invention may act asmodulators of human DC function. DC cell surface molecules known to beimportant for interaction with naive T-cell precursors, such as CD86,CD83, CD25 and HLA class II antigens may be diminished on the surface ofhuman monocyte-derived dendritic cells upon treatment with compounds ofthe present invention. Similarly, the secretion of IL-6 by mature DC maybe inhibited by the compounds of the present invention. Compound-treateddendritc cells show impaired ability to stimulate the proliferation andcytokine production of naive CD4-positive autologous T-cells.

In addition, we have found that the compounds of the present inventionmay act as specific inhibitors of IgE synthesis. Upon systemic or oraladministration a compound of the present invention may suppressimmunoglobulin synthesis, in particular the synthesis of immunoglobulinE in B-lymphocytes, i.e. a compound of the present invention may exhibitisotype specificity. Further we have found that a compound of thepresent invention may not inhibit B-cell proliferation in concentrationsbelow the concentrations needed to block IgE synthesis.

These activities can be shown in the following assays. Temperature arein degrees Celsius and are uncorrected. The following abbreviations areused: DC Dendritic cell ELISA enzyme-linked immunosorbent assay FACSfluorescence-activated cell sorting FCS fetal calf serum GM-CSFgranulocyte macrophage-colony stimulating factor IgE immunoglobulin EIL-4 interleukin-4 IL-5 interleukin-5 IL-6 interleukin-6 IL-10interleukin-10 IMDM Iscove's modified Dulbecco medium KLH keyhole limpethemocyanin Mo-DC monocyte derived dendritic cells PBMC peripheral bloodmononuclear cells SRBC sheep red blood cells RT room temperature Th Thelper cell Th2 T helper cell type 2

1. Isotype Specificity:

Inhibition of immunoglobulin synthesis induced in primary humanB-lymphocytes stimulated by cytokines and anti-CD40 antibody

Mononuclear cells are purified from normal human spleens. The resultingcell suspension contains 50-70% B-lymphocytes as judged by CD19expression in a FACS analysis. Using 96-well round-bottomed microliterplates (Costar) 5×10⁴ spleenocytes are set up in a final volume of 200μl/well in IMDM. After pre-incubation with test compound for one hourthe cells are cultured to induce IgE production for 9 days at 37° in airsupplied with 5% CO₂ in the presence of 50 ng/ml of IL-4 and 500 ng/mlof anti-CD40 antibody. The culture cell supernatants are collected andquantitated for IgE by standard isotype specific sandwich ELISA. For theinduction of IgG synthesis, the cells are cultured with 100 ng/ml IL-10and 500 ng/ml of anti-CD40 antibody for the same time period before IgGlevels are quantitated in the cell supernatants by isotype specificELISA.

In these tests the compounds of the present invention inhibit IgEproduction preferentially over IgG (IgG1).

2. B-Cell Proliferation

Normal human lymphocytes are purified from tonsils by removingcontaminating T-cells with SRBC-rosetting according to M. S. Weiner etal., Blood 42 (1973) 939. The resulting B-cells are more than 95% pureas judged by CD19 expression in a FACS analysis. Using 96-wellround-bottomed microtiter plates (Costar) 1×10⁵ spleenocytes are set upin a final volume of 200 μl/well in IMDM. After pre-incubation with testcompound for one hour, cell proliferation is induced with 50 ng/ml IL-4and 500 ng/ml anti-CD40 antibody. After a 4 day incubation period at 37°in air supplied with 5% CO₂, 1 μCl of tritiated thymidine is added andthe cells are cultured for ca. 16 hours. The cells are collected on anitrocellulose filter and the DNA-bound radioactivity is quantitated byliquid scintillation counting.

In these tests compounds of the present invention inhibit IL-4 andanti-CD40 antibody mediated B-cell proliferation above theconcentrations needed to block IgE synthesis.

3. Modulation of DC Cell Surface Markers

Human peripheral blood monocytes are prepared by elutriation or bynegative selection of PBMC using a commercially available kit(Miltenyi). The resulting monocyte population is routinely >97% positivefor CD14 as checked for purity by FACS staining for CD14. Monocytes areseeded in 6-well plates at 3×10⁶ cells/well in 5ml of IMDM mediumsupplemented with 1% FCS, streptomycin and glutamin. Generation ofimmature Mo-DC is induced by adding 40 ng/ml IL-4 and 15 ng/ml GM-CSFfor 6 days in the absence or presence of test compounds. After the first2 days, half of the volume is replaced with fresh medium, cytokines andcompounds where appropriate. On day 6 of culture, cell surfaceexpression levels of CD86 and HLA-DR is measured by FACS staining.

Maturation of DC is induced by activation of immature DC with 100 ng/mlLPS (Sigma) or by a cocktail containing 20 ng/ml GM-CSF, 100 U/ml IFN-γ,20 U/ml TNF-α and 4 μg/ml crosslinked anti-CD40 monoclonal antibodiesfor 24 hours. Then, cell surface expression levels of CD83 and CD25 wasquantitated by FACS.

In these tests, compounds of the present invention inhibit the cellsurface expression levels of CD86, HLA-DR, CD83 and CD25.

4. DC Mediated Antigen Specific Autologous T-Cell Stimulation Assay

Immature Mo-DC are generated in the absence or presence of testcompounds. Then, the cells are pulsed with 100 μg/ml KLH over night andthen co-cultured with autologous CD4-positive T-cells for nine days toelicit a primary T-cell response in the absence or presence of testcompound. After washing the cells, the primed T-cells are re-stimulatedwith fresh KLH-pulsed DC in different T/DC ratios for 3 days withoutadding compound. For the last 16 hours 1 μCl of tritiated thymidine isadded. The cells are collected on a nitrocellulose filter and theDNA-bound radioactivity is quantitated by liquid scintillation counting.In these tests, compounds of the present invention inhibit DC mediatedT-cell proliferation.

5. T-Cell Cytokine Production

Supernatants from DC/T-cell re-stimulation cultures (see above) weretaken after 48 hours and quantitated for GM-CSF and IL-2 by ELISA usingcommercially available kits. In these tests, compounds of the presentinvention inhibit DC mediated T-cell cytokine production.

6. Determination of Stability of Compounds of the Present Invention inPlasma

Heparinized blood is obtained from human volunteers and from Balb/cmice. Blood obtained is centrifuged for 4 minutes at 13,000 rpm at roomtemperature (RT) to obtain plasma. To aliquots of plasma (1 ml) testcompounds, i.e. compounds of the present invention, are added (1 μl of10 mM stock solutions in DMSO or water). The samples are incubated at37°. At various time points, aliquots of 100 μl are taken from saidsamples. An internal standard (5 μl of a 100 μg/ml solution of aninternal standard compound in methanol) is added, followed by 300 μl ofmethanol (or acetonitrile or acetonitrile/1 M HCl, as required). Samplesare centrifuged for 5 minutes at 13,000 rpm.

For analysis, 50 μI of the supernatants obtained are injected into anHPLC system (HP1090), equipped with a Hypersil BDS C-8 column (5 μm,250×4.6 mm) plus pre-column (10×4.6 mm). The column is elutedisocratically at 55° C. and at a flow rate of 1.5 ml/min with mixturesof acetonitrile and 10 mM (NH₄)₂SO₄, pH 2.7; the acetonitrile content ofthe mixtures used is in the range of 55-65% for various substances.

Analysis of specific compounds may require a different HPLC-system, e.g.column: Zorbax Extend C18 (3.5 μm, 150×4.6 mm); pre-column: HypersilBDS, C-8 (5 μm, 10×4.6 mm); RT; acetonitrile contents of solvent: 65%.

UV detection is carried out at 277 nm. For calibration, plasma samplesare spiked with a compound of formula I wherein R₄ Is hydrogen, or witha compound of formula I wherein R₄ is as defined above, but other thanhydrogen; both in the range of 0.5 to 20 μM, and internal standard.Absolute concentrations are calculated using these calibration sets.

In these determination tests we have found that a compound of formula Iwherein R₄ is as defined above, but other than hydrogen has a lowerstability in plasma than a compound of formula I wherein R₄ is hydrogen.From that it may be assumed that compounds of formula I wherein R₄ is asdefined above, but other than hydrogen, may be regarded as prodrugs ofcompounds of formula I, wherein R₄ is hydrogen. Compounds of formula I,wherein R₄ is hydrogen, on the other hand, may establish a highly activeprinciple, e.g. may establish the basic structure for the surprisingactivity of a compound of the present Invention which was found in vitroand in vivo. Compounds of formula I, wherein R₄ is hydrogen may thus beregarded as those compounds having the regular drug structure.

Compounds of the present invention show a good solubility and goodplasma levels after e.g. oral administration.

The compounds of the present invention are therefore indicated for useas modulators of DC function and inhibitors of immunoglobulin synthesis,especially inhibitors of IgE synthesis, and are useful in the treatmentof IgE-mediated diseases, particularly IgE-mediated allergic diseases,e.g. of diseases mediated by IgE expression, such as a topic dermatitis,particularly in children, urticaria, particularly acute urticaria,allergic asthma, allergic rhinitis, food allergies, allergicconjunctivitis, hayfever, bullous pemphigoid and, industrialsensitization. In addition, these compounds are indicated in otherdiseases in which inflammatory conditions play a major pathologicalrole, such as autoimmune diseases (e.g. systemic lupus erythematosus,psoriasis and rheumatoid arthritis) and gastrointestinal diseases (e.g.Crohns disease) and chronic rejection of transplants.

In another aspect the present invention provides the use of an amine,which is substituted by

-   -   phenyl-substituted pyrimidin; and    -   phenyl; and    -   a third substituent,        e.g. a compound of the present invention, in the preparation of        a medicament for the treatment of IgE-synthesis-mediated        diseases, autoimmune diseases, gastrointestinal diseases and        chronic rejection of transplants. A third substituent e.g.        includes a group R₄ as defined above.

In a preferred aspect the present invention provides the use of acompound of formula I wherein the substituents R₁ to R₄ are as definedabove in the preparation of a medicament for the treatment ofIgE-synthesis-mediated diseases, autoimmune diseases, gastrointestinaldiseases-and chronic rejection of transplants.

For the above uses the dosage to be used will vary, of course, dependinge.g. on the particular compound employed, the mode of administration andthe treatment desired. However, in general satisfactory results may beobtained when the compounds are administered at a daily dosage of fromabout 1 mg/kg to about 30 mg/kg animal body weight, suitably given individed doses two to four times daily. For most larger mammals the totaldaily dosage is from about 70 mg to about 2000 mg, convenientlyadministered, for example, in divided doses up to four times a day or inretard form. Unit dosage forms comprise, for example, from about 17.5 mgto about 1000 mg of compound in admixture with at least one solid orliquid, pharmaceutically acceptable excipient, e.g. carrier or diluent.

A compound of the present invention may be administered in similarmanner to known standards such as glucocorticoids and antihistaminicsfor use in such indications. It may be admixed with conventionaltherapeutically acceptable carriers and diluents and, optionally,further excipients, and administered e.g. orally in such forms, e.g. inthe form of tablets, capsules; or, alternatively, it may be administeredtopically, e.g. in conventional forms, such, as aerosols, ointments orcreams; parenterally or intravenously. The concentration of thesubstance will, of course vary, e.g. depending on the compoundadministered, the treatment desired and the nature of the form. Ingeneral, however, satisfactory results may be obtained in topicalapplication forms at concentrations of from about 0.05% to about 5%,particularly from about 0.1% to about 1% by weight.

In another aspect the present invention provides the use of a compoundof the present invention in the preparation of a medicament for thetherapy of IgE-mediated diseases, e.g. of diseases mediated by IgEexpression, autoimmune diseases, gastrointestinal diseases and chronictransplant rejection.

Pharmaceutical compositions for use in the therapy of IgE-mediateddiseases, autoimmune diseases, gastrointestinal diseases and chronictransplant rejection may be prepared by mixing a compound of the presentinvention together with at least one pharmaceutically acceptableexcipient, e.g. carrier or diluent.

In another aspect the present invention provides a method of treatmentof IgE-mediated diseases, autoimmune diseases, gastrointestinal diseasesand chronic transplant rejection which comprises administering atherapeutically effective amount of a compound of the present invention,e.g. in the form of a pharmaceutical composition, to a subject in needof such treatment.

A compound of the present invention may be well tolerated, as may bedetermined according to a method as conventional. A compound of thepresent invention may possess beneficial pharmacogalenical properties,such as good solubility in various solvents.

In another aspect the present invention provides a compound of thepresent invention for use as a pharmaceutical, preferably in indicationsof IgE mediated diseases, autoimmune diseases, gastrointestinal diseasesand chronic transplant rejection.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt, e.g. an acid addition salt ormetal salt; or in free form; optionally in the form of a solvate. Thecompounds of the present invention in the form of a salt exhibit thesame order of activity as the compounds of the present invention in freeform; optionally in the form of a solvate.

In another aspect the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention inassociation with at least one pharmaceutical excipient, e.g. carrier ordiluent. Such compositions may be manufactured according to a method asconventional.

A compound, or more than one compounds, of the present invention may beused for pharmaceutical treatment according to the present inventionalone, or in combination with one or more other pharmaceutically activeagents, e.g. such as useful in the treatment of IgE-mediated diseases,particularly IgE-mediated allergic diseases, e.g. of diseases mediatedby IgE expression, such as atopic dermatitis, particularly in children,urticaria, particularly acute urticaria, allergic asthma, allergicrhinitis, food allergies, allergic conjunctivitis, hayfever, bullouspemphigoid and industrial sensitization. In addition, these compoundsare indicated in other diseases in which inflammatory conditions play amajor pathological role, such as autoimmune diseases (e.g. systemiclupus erythematosus, psoriasis and rheumatoid arthritis) andgastrointestinal diseases (e.g. Crohns disease) and chronic rejection oftransplants. Such other pharmaceutically active agents include e.g.steroids, anti-histaminica, ascomycins, ASM981, rapamycins.

Combinations include fixed combinations, in which two or morepharmaceutically active agents are in the same formulation; kits, inwhich two or more pharmaceutically active agents in separateformulations are sold in the same package, e.g. with instruction forco-administration; and free combinations in which the pharmaceuticallyactive agents are packaged separately, but instruction for simultaneousor sequential administration are given.

In another aspect the present invention provides a pharmaceuticalcomposition comprising as an active ingredient a compound of the presentinvention in combination, e.g. including fixed combinations, kits andfree combinations, with one or more other pharmaceutically activeagents, e.g. which other pharmaceutically active agents are, e.g.selected from, e.g. the group consisting of, steroids, anti-histaminica,ascomycins, ASM981, rapamycins.

In the following examples which illustrate the invention references totemperature are in degrees Celsius and are uncorrected. In the ¹H-NMRchemical shifts are given in delta units; J values in Hz The followingabbreviations are used: m.p. melting point RT room temperature br. broad

EXAMPLE 1N-[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-amineA) 1-(3-Chloro-phenyl)-3-dimethylamino-propenone

A mixture of 50 g of 3-chloroacetophenone and 65 ml ofN,N-dimethylformamide dimethyl acetal is heated at ca. 100° for ca. 24hours and cooled to RT. A precipitate formed is filtrated off, washedand dried. 40 g of 1-(3-chloro-phenyl)-3-dimethylamino-propenone incrystalline form are obtained. m.p. 72.8°.

B) N-(4-Trifluoromethyl-phenyl)-quanidine carbonate

13.75 ml of aqueous 37% HCl are added dropwise to a mixture of 17.5 mlof 4-trifluoromethylaniline and 28 ml of water, the mixture obtained ispreheated to ca. 75° for ca. 20 minutes. To the mixture obtained asolution of 12.9 g of cyanamide in 13 ml of water is added drop%wise atca. 75° and stirring is continued for ca. 4 hours at that temperature.The mixture obtained is cooled to RT and a solution of 9.26 g of Na₂CO₃in 43 ml of water are added dropwise. To the mixture obtained 140 ml ofwater are added and the mixture obtained is stirred overnight. A solidprecipitates, is filtrated off, washed and dried. 14 g ofN-(4-trifluoromethyl-phenyl)-guanidine carbonate in crystalline form areobtained. m.p. 125.3°.

C)N-[4-(3Chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-amine

A mixture of 1.5 g of 1-(3-chloro-phenyl)-3-dimethylamino-propenone, 1.7g of of N-(4-trifluoromethyl-phenyl)-guanidine carbonate and 15 ml ofn-butanol is heated at 120° for ca. 24 hours, the mixture obtained iscooled to RT and a solid precipitates. The precipitate is filtrated offand is re-crystallised from n-butanol. 1.0 g ofN-[4-(3-chlorophenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)aminein crystalline form are obtained. m.p. 201.5°.

Analogously as described in example 1 but using appropriate startingmaterial, compounds of formula

wherein R_(1EX), R_(2EX) and R_(3EX) are as defined in TABLE 1 below andR_(4EX) is H, having a melting point m.p. as defined in TABLE 1 beloware obtained: TABLE 1 Example R_(1EX) R_(2EX) R_(3EX) m.p. (°) 2 CF₃ CF₃F 168.0 3 Cl CF₃ Cl 182.3 4 CF₃ CF₃ Cl 161.8 5 CF₃ H CF₃ 185.9

Starting from a compound of formula

wherein R₄ is hydrogen, which is the compoundN-[4-(3-chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-amine,compounds of the following examples 6 to 68, wherein R₄ is as defined insaid examples, may be obtained.

EXAMPLE 6 Compound of formula II_(Ex), wherein R_(4EX) is a group offormula—CO—CH₃N-[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-acetamide

A solution of 1.6 g of a compound of formula II_(EX) wherein R₄ ishydrogen and 300 mg of 4-dimethylaminopyrimidine in 30 ml of drypyridine is treated with acetic acid anhydrid and stirred at 70°. Fromthe mixture obtained solvent is evaporated off, diethyl ether is addedand a precipitate obtained is removed by filtration. The filtrateobtained is concentrated and the concentrate obtained is subjected tosilicagel medium pressure chromatography.N-[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-acetamideis obtained in solid (crystalline) form from a mixture of toluene andpentane in the form of a powder. m.p. 128.6-129.6°.

Analogously to the method as described in example 6, but usingappropriate starting materials, compounds of formula II_(EX), whereinR_(4EX) is as set out in TABLE 2 below, having ¹H-NMR or m.p. data asdefined in TABLE 2 are obtained: TABLE 2 Example R_(4EX) m.p./¹H-NMR 7—CO—CH₂—CH₃ 121.1° 8 —CO—CH(CH₃)₂   122-122.8° 9 —CO—C₆H₅ 130.1° 10—CO—CH₂—CH(CH₃)₂ 109-110° 11 —CO—CO—C₆H₅ 144.9° 12 —CO—C(CH₃)₃103.9-104.7° 13

136.8° 14

158.8° 15 —CO—CO—O—CH₂—CH₃ 133.7° 16 —CO—CH₂—O—CO—CH₃ 150.8° 17—CO—CO—O—CH₃ 141.3° 18

94.5-95.8° 19 —CO—CH₂—O—CH₃ 124.6° 20

¹H-NMR (d₆-DMSO, 400MHz, RT): 8.96 (d, J=5.3, 1H), 8.15 (d, J=5.3, 1H),7.95 (d, J=8.3, 2H), 7.70 (t, J=7.8, 1H), 7.60 (d, J=8.2, 2H), 5.97 (q,J=6.7, 1H), 2.06 (s, 3H), 1.69 (d, J=6.7, 3H)

EXAMPLE 21 Compound of formula II_(EX), wherein R_(4EX) is a group offormula

4-(3-Chloro-phenyl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-carbamicacid 3-((S)-2-tert.-butoxycarbonylamino-propionylamino)-propyl ester inthe form of a free base and in the form of a hydrochloride

0.5 g of a solution of a compound of formula II_(EX) wherein R₄ ishydrogen in 30 ml of dry chlorobenzene is treated with a solution of0.76 ml of 20% phosgene in toluene. The mixture obtained is stirred at130°, a clear solution obtained is cooled to 100° and a further solutionof 0.76 ml of 20% phosgene in toluene is added. The mixture obtained isstirred at 130°, cooled to 100° and treated with argon in order toremove excess phosgene. To the mixture obtained a solution of 144 μl of[(S)-1-(3-hydroxy-propylcarbamoyl)-ethyl]-carbamic acid tert-butyl esterand 130 μl of pyridine in 5 ml of chlorobenzene is added, the mixtureobtained is stirred at 130° and cooled to RT. The mixture obtained iswashed with 1N aqueous HCl, aqueous, saturated NaHCO₃ solution and brineand concentrated. The concentrate obtained is subjected to flashchromatography on silicagel.[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-carbamicacid 3-((S)-2-tert.-butoxycarbonylamino-propionylamino)-propyl ester isobtained in the form of an oil.

¹H-NMR (CDCl₃, 400 MHz, RT) δ: 8.77(d;1H), 7.94(s;1H), 7.83(d;1H),7.69(d;1H), 7.51(d; 1H), 7.50-7.38(m;4H), 4.35(t;2H), 3.16(m;2H),1.84(m;2H), 1.43(s;9H).

276 mg of a solution of[4-(3-chloro-phenyl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-carbamicacid 3-((S)-2-tert.-butoxycarbonylamino-propionylamino)-propyl ester intrifluoroacetic acid is stirred for ca. 2 hours. From the mixtureobtained solvent is evaporated off and the evaporation residue obtainedis dissolved in diethyl ether. The mixture obtained is treated with HClin diethyl ether.[4-(3—Chloro-phenyl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-carbamicacid 3-((S)2-tert.-butoxycarbonylamino-propionylamino)-propyl ester inthe form of a hydrochloride precipitates, is filtrated off, washed anddried. m.p.: 54.6-54.8°.

Analogously to the method as described in example 21, but usingappropriate starting materials, compounds of formula II_(EX), whereinR_(4EX) is as described in TABLE 3 below, having ¹H-NMR or m.p. data asdefined in TABLE 3 are obtained: TABLE 3 Example R_(4EX) m.p./¹H-NMR 22

65.7-72.9° 23

192.5-194.2° 24

191.9-193.7° 25

126.8-130.8° 26

  161-162.8° 27

138.1-143.2° 28

¹H-NMR (d₆-DMSO, 400 MHz, RT) δ: 8.86 (d; 1H), 8.44 (bd; 3H), 8.15 (m;1H), 8.10 (m; 1H), 8.06 (d; 1H), 7.76/7.51 (AB-system; 4H), 7.64 (m;1H), 7.57 (t; 1H), 4.62-4.36 (m; 3H), 4.32- 4.28 (m; 1H), 4.02-3.98 (m;1H), 1.26 (d; 3H)  29a

  133-136.3°  29b as in example 29a 185.6-187.1° 30

91.9-95°   31

¹H-NMR (d₆-DMSO): 8.85 (d; 1H), 8.23 (br; 2H), 8.14 (m; 1H), 8.10 (m;1H), 8.06 (d; 1H), 7.76 (d; 2H), 7.64 (m; 1H), 7.59 (t; 1H), 7.49 (d;2H), 4.28 (m; 2H), 4.12 (m; 2H), 4.07 (q, 1H), 1.93 (m; 2H), 1.34 (d;3H)

In TABLE 3 the m.p. or ¹H-NMR data is the data of the compounds ofexamples 22 to 28, 29a and 30 in the form of hydrochlorides, for example29b in the form of the besylate and for example 31 in the form of thetrifluoroacetate.

EXAMPLE 32a Compound of formula II_(EX), wherein R_(4EX) is a group offormula

[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-carbamicacid 2-[(2-hydroxy-ethyl)-methyl-amino]-ethyl ester in the form of ahydrochloride 0.5 g of a solution of a compound of formula II_(EX)wherein R₄ is hydrogen in 30 ml of dry chlorobenzene is treated with asolution of 0.76 ml of 20% phosgene in toluene. The mixture obtained isstirred at 130°, a clear solution obtained is cooled to 100° and afurther solution of 0.76 ml of 20% phosgene in toluene is added. Themixture obtained is stirred at 130°, cooled to 100° and treated withargon in order to remove excess phosgene. The mixture obtained istreated at RT with 0.675 ml of a solution of2-[(2-hydroxy-ethyl)methyl-amino]-ethanol in 5 ml of chlorobenzene andstirred at 130°, cooled to RT and concentrated in vacuum. Theconcentration residue obtained is dissolved in ethyl acetate and washedwith aqueous, saturated NaHCO₃ solution and brine. The organic layerobtained is treated with acetic acid, the mixture obtained isconcentrated in vacuum and the concentrate obtained is subjected tochromatography.[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-carbamicacid 2-[(2-hydroxy-ethyl)-methyl-amino]-ethyl ester in the form of anacetate obtained is dissolved in diethylether and treated with HCl indiethyl ether.[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-carbamicacid 2-[(2-hydroxy-ethylymethyl-amino]-ethyl ester in the form of ahydrochloride precipitates (crystallizes), is filtrated off, washed anddried. m.p.: 145.9-147.7°.

Analogously to the method as described in example 32a, but usingappropriate starting materials, compounds of formula II_(EX), whereinR_(4EX) is as described in TABLE 4 below, having ¹H-NMR or m.p. data asdefined in TABLE 4 are obtained: TABLE 4 Example R_(4EX) m.p./¹H-NMR 32bas in example 32a 119.5° 32c as in example 32a 190.2-190.7° 32d as inexample 32a 66.5-72.2° 32e as in example 32a 134.1-135.5° 32f as inexample 32a 130.4-132.5° 33 —CO—O—CH₂—CH₃ 68.3-69.2° 34

151.3-154.3° 35

171.2-174.3° 36

128.9-129.1° 37

¹H-NMR (DMSO-d6, 400MHz, RT) δ: 8.85 (d; 1H), 8.15 (m; 1H), 8.10 (m;1H), 8.04 (d; 1H), 7.75/7.48 (AB-system, 4H); 7.63 (m; 1H), 7.57 (t;1H), 4.46 (t; 1H), 4.25 (t; 2H), 3.34 (dt; 2H), 1.69 (d; 2H) 38

152.7-156.2° 39

154.9-162.8° 40

¹H-NMR (d₆-DMSO, 400MHz, RT) δ: 8.86 (d; 1H), 8.11-8.05 (m; 3H), 7.79(d; 2H); 7.64-7.57 (m; 4H), 4.62 (bs; 2H), 3.60-3.40 (m; 8H), 3.40-3.25(m; 2H), 2.76 (s; 3H)

In TABLE 4 the m.p. or ¹H-NMR data of examples 33, 37 and 40 is the dataof the compounds in free base form, the m.p. or ¹H-NMR data of examples34, 35, 36, 38 and 39 is the data of the compounds in the form ofhydrochlorides, the m.p. of example 32b to 32f) are the date for thefollowing salts: 32b) mesylate, 32c) sulfate, 32d) tartrate, 32e)p-toluenesulfonate and 32f) besylate.

EXAMPLE 41 Compound of formula II_(EX), wherein R_(4EX) is—CH₃[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-methyl-(4-trifluoromethyl-phenyl)-amine

A solution of 160 mg of a compound of formula II_(EX) wherein R₄ ishydrogen in 4 ml of dry dimethylformamide is treated with NaH, themixture obtained is stirred at 100°, cooled to RT and treated with 57 μlof methyliodide. The mixture obtained is stirred overnight at RT. Fromthe mixture obtained a precipitate is filtrated off and the filtrateobtained is concentrated in vacuum. The concentration residue obtainedis subjected to flash chromatography on silicagel.[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-methyl-(4-trifluoromethyl-phenyl)-amineobtained is precipitated from n-pentane in the form of a solid,filtrated off and dried. Structure confirmed by ¹H-NMR data.

Analogously to the method as described in example 41, but usingappropriate starring materials, compounds of formula II_(EX), whereinR_($EX) is CH₃ is prepared.

EXAMPLE 42 ¹H-NMR: 8.55 (d, J=5.2 Hz, 1H); 7.49 (d, 1H); 3.59 (s, 3H)EXAMPLE 43 R_(4EX) is —CO—N(CH₃)₂

A mixture of 0.5 g ofN-[4-(3-chloro-phenyl)-pyrimidin-2-yl-N-(44trifluoromethyl-phenyl)-amine,86 mg of NaH, 0.4 ml of N,N-dimethylcarbamoylchloride in 5 ml ofN,N-dimethylformamide is heated for 4 hours at 80°. Solvent isevaporated and to a residue obtained ethylacetate is added. Afterwashing and drying a concentrate obtained is chromatographed onsilicagel and the product is obtained. m.p. 143°.

EXAMPLE 44

A mixture of 1 g ofN-[4-(3-chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-amine,1.98 ml of glutaric acid monomethyl ester chloride, 1.1 ml pyridine and10 mg of dimethylaminopyridine in 25 ml of toluene is heated. Themixture is diluted with ethyl acetate, washed with cold 0.01 N aq HCl,aq. bicarbonate and brine. The organic phase is dried, solventevaporated and the product is obtained. (d₆-DMSO, 500 MHz, RT): 8.83 (d,J=5.2, 1H); 8.12-8.10 (m, 1H); 8.10-8.07 (m, 1H); 8.02 (d, J=5.2, 1H);7.79 (d, J=8.5, 2H) 7.65-7.62 (m, 1H); 7.57 (t, J=7.8, 1H); 747 (d,J=8.2, 2H); 3.53 (s, 3H); 2.84 (t, J=7.3, 2 H); 2.38 (t, J=7.5, 2H);1.89 (quintett, J=7.3, 2H)

Analogously as described in example 44 but using appropriate startingmaterial, compounds of formula I, wherein R_(4EX) is as described inTABLE 5 below, having ¹H-NMR (d₆-DMSO, 500 MHz, RT, unless givenotherwise) or m.p. as defined in TABLE 5 are obtained: TABLE 5 ExampleR_(4EX) m.p./¹H-NMR 45

8.83 (d, J=5.2, 1H); 8.12-8.11 (m, 1H); 8.10-8.08 (m, 1H); 8.02 (d,J=5.2, 1H); 7.78 (d, J=8.5, 2H); 7.65-7.62 (m, 1H); 7.58 (t, J=7.9, 1H);7.45 (d, J=8.3, 2H); 3.54 (s, 3H); 2.79 (t, J=7.5, 2H); 2.29 (m, 2H);1.68-1.62 (m, 2H); 1.52-1.48 (m, 2H) 46

(400MHz): 8.84 (d, J=5.3, 1H); 8.13- 8.09 (m, 2H); 8.02 (d, J=5.3, 1H);7.80 (d, J=8.4, 2H); 7.64-7.62 (m, 1H); 7.57 (t, J=7.8, 1H); 7.46 (d,J=8.2, 2H); 3.59 (s, 3H); 3.12-3.08 (m, 2H); 2.68-2.65 (m, 2H) 47

8.77 (d, J=5.5, 1H); 8.08-8.07 (m, 2H); 7.96 (d, J=5.2, 1H); 7.83 (d,J=8.5, 2H); 7.65-7.62 (m, 1H); 7.57 (t, J=8.1, 1H); 7.51 (d, J=8.2, 2H);4.90 (s, 2H); 4.22 (s, 2H); 3.61 (s, 3H) 48

8.79 (d, J=5.5, 1H); 8.11-8.10 (m, 1H); 8.09-8.08 (m, 1H); 7.98 (d,J=5.2, 1H); 7.81 (d, J=8.2, 2H); 7.65-7.62 (m, 1H); 7.58 (t, J=8.1, 1H);7.47 (d, J=8.2, 2H); 4.72 (s, 2H), 3.56-3.54 (m, 2H); 3.34- 3.32 (m,2H); 3.14 (s, 3H)

EXAMPLE 49a

0.01 N aqueous NaOH is added dropwise to a solution of 4.5 gN-[4-(3-chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-aminein a mixture of tetrahydrofuran and water. A precipitate formed isfiltered off and solvent is evaporated. The evaporation residue obtainedis filtered and a filtrate obtained is acidified to pH 2 with 0.1 N HCland extracted with ethylacetate. The organic phase is washed and driedand solvent is stripped off to give a solid. Crystallisation from amixture dichloromethane and pentane results in the product. m.p.: 138.6°C. ¹H-NMR: (d₆-DMSO, 500 MHz, RT): 12.01 (br, 1H); 8.83 (d, J=5.2, 1H);8.10 (m, 1H); 8.09-8.07 (m, 1H); 8.01 (d, J=5.4, 1H); 7.78 (d, J=8.7,2H); 7.63-7.61 (m, 1H); 7.56 (t, J=7.8, 1H); 7.47 (d, J=8.7, 2H); 2.84(t, J=7.5, 2H); 2.29 (t, J=7.4, 2H); 1.87 (quintett, J=7.3. 2H)

EXAMPLE 49b

40 mg of calcium hydroxide are added to a mixture of 0.5 g of a compoundof example 49a, 11 ml of tetrahydrofuran and 5 ml of water. A mixtureobtained is shaken for a few minutes and left at RT. Crystals separatedare filtered and washed with cold isopropanol to give the calcium saltof a compound of example 49a.

¹H-NMR (d₆-DMSO, 400 MHz, RT): 8.83 (d, J=5.3); 8.00 (d, J=5.3); 7.78(d, J=8.5); 7.45 (d, J=8.3); 2.78 (t, J=7.5); 1.99 (t, J=7.3); 1.8 (m)

Analogously as described in example 49a but using appropriate startingmaterial, compounds of formula I, wherein R_(4EX) is as described inTABLE 6 below, having ¹H-NMR (d₆-DMSO, 500 MHz, RT) or m.p. as definedin TABLE 6 are obtained: TABLE 6 Example R_(4EX) m.p./¹H-NMR 50

11.98 (br, 1H); 8.83 (d, J=5.3, 1H); 8.12-8.11 (m, 1H); 8.10-8.08 (m,1H); 8.01 (d, J=5.3, 1H); 7.78 (d, J=8.3, 2H); 7.65-7.62 (m, 1H); 7.57(t, J=7.8, 1H); 7.45 (d, J=8.3, 2H); 2.79 (t, J=7.5, 2H); 2.19 (t,J=7.3, 2H); 1.69- 1.63 (m, 2H); 1.56-1.50 (m, 2H) 51

8.82 (d, J=5.5, 1H); 8.15 (d, J=7.3, 1H); 8.12-8.08 (m, 2H); 8.00 (d,J=5.2, 1H); 7.78 (d, J=8.2, 2H); 7.65- 7.62 (m, 1H); 7.57 (t, J=7.8,1H); 7.46 (d, J=8.2, 2H); 4.16 (quintett, J=7.2, 1H); 3.05-2.95 (m, 2H);2.58-2.52 (m, 2H); 1.22 (d, J=7.3, 3H) 52

12.40 (br., 1H); 8.83 (d, J=5.5, 1H); 8.11-8.08 (m, 2H); 8.05 (d, J=7.3,1H); 8.02 (d, J=5.5, 1H); 7.78 (d, J=8.5, 2H); 7.64-7.62 (m, 1H); 7.57(t, J=7.8, 1H); 7.47 (d, J=8.2, 2H); 4.16- 4.09 (m, 1H); 2.80-2.76 (m,2H); 2.16 (t, J=7.3, 2H); 1.89-1.81 (m, 2H); 1.17 (d, J=7.3, 3H) 53

8.78 (d, J=5.2, 1H); 8.09-8.06 (m, 2H); 7.97 (d, J=5.2, 1H); 7.95 (d,J=7.5, 1H); 7.83 (d, J=8.5, 2H); 7.64- 7.62 (m, 1H); 7.57 (t, J=7.8,1H); 7.52 (d, J=8.5, 2H); 4.90 (s, 2H); 4.26- 4.18 (m, 1H); 4.01 (s,2H); 1.24 (d, J=7.0, 3H)

EXAMPLE 54

1.97 ml of diisopropylethyl amine are added dropwise to a mixture of 2 gofN-[4-(3-chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-amine,1.21 ml of succinyl chloride and 10 mg of dimethylaminopyridine inCH₂Cl₂. The mixture is stirred at RT, cooled and 2 g of L-alanine methylester hydrochloride are added. 3.4 ml of diisopropyl ethylamine areadded dropwise to the mixture and stirred further. The mixture obtainedis diluted with ethylacetate, washed and dried. Solvent is evaporatedand the product is obtained after crystallisation (m.p. 170.9° C.).

(d₆-DMSO, 500 MHz, RT): 8.83 (d, J=5.3, 1H); 8.31 (d, J=7.0, 1H);8.12-8.08 (m, 2H); 8.01 (d, J=5.3, 1H); 7.79 (d, J=8.4, 2H); 7.64-7.62(m, 1H); 7.57 (t, J=7.9, 1H); 7.46 (d, J=8.2, 2H); 4.24 (quintett,J=7.2, 1H); 3.58 (s, 3H); 3.04-2.98 (m, 2H); 2.60-2.51 (m, 2H); 1.24 (d,J=7.3, 3H)

Analogously as described in example 54 but using appropriate startingmaterial, compounds of formula I, wherein R₄ is as described in TABLE 7below, having ¹H-NMR (d₆-DMSO, 500 MHz, RT) or m.p. as defined in TABLE7 are obtained: TABLE 7 Example R_(4EX) m.p./¹H-NMR 55

12.61 (br.); 8.82 (d, J=5.3, 1H); 8.09- 8.06 (m, 3H); 8.01 (d, J=5.2,1H); 7.78 (d, J=8.7, 2H); 7.63-7.61 (m, 1H); 7.58- 7.54 (m, 1H); 7.45(d, J=8.3, 2H); 7.21-7.13 (m, 5H); 4.40-4.35 (m, 1H); 3.00 (dd, J=13.9,4.8, 1H); 2.79 (dd, J=13.8, 9.7, 1H); 2.69 (t, J=7.3, 2H); 2.12-2.08 (m,2H); 1.79 (quintet, J=7.3, 2H) 56

8.82 (d, J=5.5, 1H); 8.13-8.12 (m, 1H); 8.11-8.09 (m, 1H); 8.00 (d,J=5.2, 1H); 7.79 (d, J=8.2, 2H); 7.65-7.62 (m, 1H); 7.57 (t, J=7.9, 1H);7.46 (d, J=8.2, 2H); 3.35-3.21 (m, 4H); 2.99-2.96 (m, 2H); 2.70-2.67 (m,2H); 1.09 (t, J=7.0, 3H); 0.98 (t, J=7.0, 3H) 57

8.82 (d, J=5.3, 1H); 8.12-8.07 (m, 2H); 8.00 (d, J=5.3, 1H); 7.83 (t,J=5.6, 1H); 7.78 (d, J=8.8, 2H); 7.63 (m, 1H); 7.56 (t, J=7.8, 1H); 7.45(d, J=8.6, 2H); 3.04- 2.96 (m, 4H); 2.45 (m); 2.17 (t, J=7.2, 2H); 2.07(s, 6H); 1.47 (quintett, J=7.1, 2H) 58

(400MHz): 8.82 (d, J=5.3, 1H); 8.31 (d, J=7.7, 1H); 8.11-8.08 (m, 2H);8.01 (d, J=5.3, 1H); 7.77 (d, J=8.7, 2H); 7.64- 7.61 (m, 1H); 7.56 (t,J=7.7, 1H); 7.44 (d, J=8.2, 2H); 4.28-4.23 (m, 1H); 3.58 (s, 3H); 2.97(m, 2H); 2.62-2.48 (m); 2.25 (t, J=7.5, 2H); 1.90 (m, 1H); 1.75 (m, 1H)59

12.64 (br); 8.82 (d, J=5.2, 1H); 8.21 (d, J=8.0, 1H); 8.11-8.07 (m, 2H);8.01 (d, J=5.3, 1H); 7.77 (d, J=8.5, 2H); 7.64- 7.61 (m, 1H); 7.56 (t,J=7.9, 1H); 7.45 (d, J=8.3, 2H); 7.22-7.11 (m, 5H); 4.40 (dt, 1H); 3.01(dd, J=13.8, 5.1, 1H); 2.92-2.88 (m, 2H); 2.83 (dd, J=13.7, 9.1, 1H);2.55-2.43 (m) 60

8.83 (d, J=5.3, 1H); 8.30 (d, J=7.5, 1H); 8.12-8.08 (m, 2H); 8.01 (d,J=5.3, 1H); 7.78 (d, J=8.9, 2H); 7.64-7.62 (m, 1H); 7.57 (t, J=7.9, 1H);7.45 (d, J=8.4, 2H); 4.27 (dt, J=5.3, 8.3, 1H); 3.59 (s, 3H); 3.55 (s,3H); 3.04-2.96 (m, 2H); 2.62-2.49 (m, 2H); 2.38-2.31 (m, 2H); 1.99-1.92(m, 1H); 1.83-1.76 (m, 1H) 61

8.83 (d,J=5.2, 1H); 8.19 (d, J=7.5, 1H); 8.11-8.07 (m, 2H); 8.02 (d,J=5.3, 1H); 7.78 (d, J=8.6, 2H); 7.64-7.62 (m, 1H); 7.57 (t, J=7.8, 1H);7.47 (d, J=8.1, 2H); 4.22-4.18 (m, 1H); 3.55 (two singlets, 6H); 2.78(t, J=7.4, 2H); 2.30 (t, J=7.8, 2H); 2.18 (t, J=7.2, 2H); 1.96- 1.84 (m,3H); 1.80-1.72 (m, 1H) 62

8.83 (d, J=5.2, 1H); 8.10-8.07 (m, 2H); 8.05 (d, J=7.6, 1H); 8.01 (d,J=5.2, 1H); 7.78 (d, J=8.9, 2H); 7.63-7.61 (m, 1H); 7.57 (t, J=7.9, 1H);7.47 (d, J=8.5, 2H); 4.15 (dt, J=5.0, 8.4, 1H); 3.54 (s, 3H); 2.78 (m,2H); 2.30-2.27 (m, 2H); 2.18 (t, J=7.3, 2H); 1.96-1.90 (m, 1H);1.88-1.82 (m, 2H); 1.78-1.70 (m, 1H) 63

8.83 (d, J=5.5, 1H); 8.20 (d, J=7.0, 1H); 8.11-8.08 (m, 2H); 8.02 (d,J=5.2, 1H); 7.78 (d, J=8.2, 2H); 7.65-7.62 (m, 1H); 7.57 (t, J=7.9, 1H);7.47 (d, J=7.9, 2H); 4.21-4.15 (m, 1H); 3.54 (s, 3H); 2.78 (t, J=7.5,2H); 2.16 (t, J=7.3, 2H); 1.89-1.82 (m, 2H); 1.18 (d, J=7.3, 3H) 64

8.78 (d, J=5.3, 1H); 8.15 (d, J=7.3, 1H); 8.09-8.07 (m, 2H); 7.97 (d,J=5.3, 1H); 7.84 (d, J=8.3, 2H); 7.65-7.62 (m, 1H); 7.58-7.55 (m, 1H);7.52 (d, J=8.3, 2H); 4.90 (s, 2H); 4.35-4.28 (m, 1H); 4.02 (s, 2H); 3.58(s, 3H); 1.25 (d, J=7.3, 3H) 65

8.82 (d, 1H); 8.12-8.07 (m, 2H); 8.02 (d, J=7.8, 1H); 8.00 (d, J=5.3,1H); 7.84 (m, 1H); 7.77 (d, J=8.4, 2H); 7.63-7.61 (m, 1H); 7.55 (t, 1H);7.45 (d, J=8.2, 2H); 4.12-4.07 (m, 1H); 3.01-2.97 (m, 4H); 2.48-2.45 (m,2H); 1.80 (s, 3H) 66

8.82 (d, 1H); 8.12-8.07 (m, 2H); 8.00 (d, J=5.3, 1H); 7.78 (d, J=8.3,2H); 7.63 (m, 1H); 7.56 (t, J=7.9, 1H); 7.45 (d, J=8.1, 2H); 3.25-3.16(m, 4H); 2.80 (t, J=7.3, 2H); 2.31 (t, J=7.3, 2H); 1.85 (quintett,J=7.3, 2H); 1.00 (t, J=7.1, 3H); 0.92 (t, J=7.1, 3H) 67

8.83 (d, J=5.3, 1H); 8.11-8.07 (m, 2H); 8.01 (d, J=5.3, 1H); 7.80-7.73(m, 3H); 7.62 (d, 1H); 7.55 (t, 1H); 7.45 (d, J=8.3, 2H); 2.95 (m, 2H);2.75 (t, J=7.2, 2H); 2.05 (s)

EXAMPLE 68

A solution 6.5 g of 3-[5-(2-Chlorocarbonyl-ethoxy)-pentyloxy]-propionylchloride in 10 ml of CH₂Cl₂ is added dropwise to a mixture of 1 g ofN-[4-3-chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-amine,10 mg of dimethylaminopyridine and 2.7 ml of diisopropyl ethylamine inCH₂Cl₂. The mixture obtained is stirred at RT, cooled and acetonitrileand water are added; the mixture is stirred further. The mixtureobtained is extracted with ethylacetate. An organic phase formed iswashed, dried, solvent is stripped off and the product is obtained.¹H-NMR (d₆-DMSO, 500 MHz, RT): 8.83 (d, J=5.2, 1H); 8.12 (t, J=1.9, 1H);8.10 (dt, J=7.6, 1.5, 1H); 8.02 (d, J=5.4, 1H); 7.79 (d, J=8.3, 2H);7.64 (m, 1H); 7.57 (t, J=7.9, 1H); 7.44 (d, J=8.1, 2H); 3.68 (t, J=6.4,2H); 3.51 (t, J=6.4, 2H); 3.03 (t, J=6.5, 2H); 2.39 (t, J=6.3, 2H);1.47-1.39 (m, 4H); 1.28-1.21 (m, 2H)

1. A compound of formula

wherein R₁ is halogen or halo(C₁₋₄)alkyl, R₂ is hydrogen, halogen orhalo(C₁₋₄)alkyl, R₃ is halogen or halo(C₁₋₄)alkyl, R₄ is hydrogen,(C₁₋₈)alkyl, hydroxy(C₁₋₆)alkyl or a group of formula —CO—R₅,—CO—(CH₂)_(m)—OR₆, —CO—CO—R₇, —CO—CO—OR₈, —CO—N(R₉R₁₀),—CO—(CH₂)_(n)—CO—R₁₁, —CO—(CHR₁₅)—O—(CH₂)_(o)—CO—R₁₁,—CO—(CH₂)_(p)—O—(CH₂)_(q)—O—(CH₂)_(r)—R₁₆, —CO—O—(CH₂)_(s)—O—CO—R₁₇,—CO—O—(CH₂)_(t)—N(R₁₈R₁₉), —CO—O—(CH₂)_(u)—NH—CO—CH(NH₂)—R₂₀, or—CO—O—(CH₂)_(w)—NH—CO—R₁₇, wherein R₅ is hydrogen, (C₁₋₈)alkyl,(C₃₋₈)cycloalkyl, amino, (C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, aryl orheterocyclyl which is a 5 or 6-membered heterocyclic ring system having1 to 4 heteroatoms selected from N, O or S, R₆ is hydrogen, (C₁₋₄)alkyl,(C₃₋₈)cycloalkyl, aryl, (C₁₋₄)alkyl substituted by heterocyclyl which isa 5 or 6-membered heterocyclic ring system having 1 to 4 heteroatomsselected from N, O or S, amino(C₁₋₆)alkyl, (C₁₋₄)alkylamino(C₁₋₆)alkyl,di(C₁₋₄)alkylamino(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,hydroxy(C₁₋₄)alkylamino(C₁₋₆)alkyl or an amino acid residue, R₇ and R₈independently of each other are (C₁₋₄)alkyl, (C₃₋₈)cycloalkyl, aryl orheterocyclyl which is a 5 or 6-membered heterocyclic ring system having1 to 4 heteroatoms selected from N, O or S, R₉ and R₁₀ independently ofeach other are hydrogen or (C₁₋₄)alkyl or one of R₉ and R₁₀ is hydrogenand the other is (C₃₋₈)cycloalkyl, (C₁₋₄)alkyl, aryl or heterocyclyl,R₁₁ is (C₁₋₄)alkyl, —OR₁₂, —NR₁₃R₁₄, an amino acid, an (C₁₋₄)alkylesterthereof or a di(C₁₋₄)alkylester thereof, R₁₂ is hydrogen or (C₁₋₄)alkyl,R₁₃ and R₁₄ independently of each other are hydrogen, (C₁₋₄)alkyl,amino(C₁₋₆)alkyl, (C₁₋₄)alkylamino(C₁₋₆)alkyl,di(C₁₋₄)alkylamino(C₁₋₆)alkyl, R₁₅ is hydrogen or (C₁₋₄)alkyl, R₁₆ ishydrogen, (C₁₋₄)alkyl, carboxyl or carboxylic ester, R₁₇ isamino(C₁₋₄)alkyl, (C₁₋₄)alkylamino(C₁₋₄)alkyl ordi(C₁₋₄)alkylamino(C₁₋₄)alkyl, R₁₈ is hydrogen or (C₁₋₄)alkyl, R₁₉ ishydroxy(C₁₋₄)alkyl, R₂₀ is (C₁₋₄)alkyl or hydroxy(C₁₋₄)alkyl, m is 0 to4, n is 2 to 8, o is 0 to 4, p is 0 to 4, q is 1 to 8, r is 0 to 4, s is1 to 4, t is 1 to 4, u is 1 to 6 and w is 1 to
 6. 2. A compound of claim1 wherein R₁ is chloro or trifluoromethyl, R₂ is hydrogen ortrifluoromethyl, R₃ is chloro, fluoro or trifluoromethyl, R₄ ishydrogen, (C₁₋₄)alkyl, e.g. methyl, hydroxy(C₁₋₄)alkyl, e.g.hydroxyethyl, or a group of formula —CO—R₅, —CO—(CH₂)_(m)—OR₆,—CO—CO—R₇, —CO—CO—OR₈, —CO—N(R₉R₁₀), —CO—(CH₂)_(n)—CO—R₁₁,—CO—(CHR₁₅)—O—(CH₂)_(o)—CO—R₁₁,—CO—(CH₂)_(p)—O—(CH₂)_(q)—O—(CH₂)_(r)—R₁₆, —CO—O—(CH₂)_(s)—O—CO—R₁₇,—CO—O—(CH₂)_(t)—N(R₁₈R₁₉), —CO—O—(CH₂)_(u)—NH—CO—CH(NH₂)—R₂₀, or—CO—O—(CH₂)_(w)—NH—CO—R₁₇, wherein R₅ is hydrogen, (C₁₋₄)alkyl,(C₃₋₆)cycloalkyl, dimethylamino, phenyl or heterocyclyl which is a6-membered heterocyclic ring system having one O as a heteroatom, e.g.tetrahydropyranyl, R₆ is hydrogen, (C₁₋₄)alkyl, (C₁₋₂)alkyl substitutedby heterocyclyl which is a 5 or 6-membered heterocyclic ring systemhaving 1 or 2 heteroatoms selected from N or O, e.g. includingunsubstituted pyrrolidine, morpholine and piperazine and piperazinesubstituted by e.g. (C₁₋₂)alkyl or (C₁₋₂)hydroxyalkyl; amino(C₁₋₄)alkyl,(C₁₋₂)alkylamino(C₁₋₄)alkyl, di(C₁₋₂)alkylamino(C₁₋₄)alkyl,hydroxy(C₁₋₃)alkyl, hydroxy(C₁₋₂)alkylamino(C₁₋₂)alkyl or an amino acidresidue, R₇ and R₈ independently of each other are (C₁₋₂)alkyl orphenyl, R₉ and R₁₀ independently of each other are hydrogen or(C₁₋₂)alkyl, R₁₁ is (C₁₋₂)alkyl, —OR₁₂, —NR₁₃R₁₄, an amino acid, an(C₁₋₂)alkylester thereof or an di(C₁₋₂)alkylester thereof, R₁₂ ishydrogen or (C₁₋₂)alkyl, R₁₃ and R₁₄ independently of each other arehydrogen, (C₁₋₂)alkyl, amino(C₁₋₄)alkyl, (C₁₋₂)alkylamino(C₁₋₄)alkyl,di(C₁₋₂)alkylamino(C₁₋₄)alkyl, R₁₅ is hydrogen or (C₁₋₂)alkyl, R₁₆ ishydrogen, (C₁₋₂)alkyl, carboxyl or carboxylic ester, R₁₇ isamino(C₁₋₂)alkyl, R₁₈ is hydrogen or (C₁₋₂)alkyl, R₁₉ ishydroxy(C₁₋₂)alkyl, R₂₀ is (C₁₋₂)alkyl or hydroxy(C₁₋₂)alkyl, m is 0 or1, n is 2 to 4, o is 0 or 1, p is 0 to 2, q is 2 to 5, r is 0 to 2, s is2, t is 2, u is 1 to 3 and w is 1 to
 3. 3. A compound according to claim1 which is a compound of formula I wherein R₁ is chloro, R₂ is hydrogen,R₃ is trifluoromethyl and R₄ is hydrogen.
 4. A compound according toclaim 1 which is a compound of formula I wherein R₁ is chloro, R₂ ishydrogen, R₃ is trifluoromethyl and R₄ is a group of formula—CO—O—(CH₂)₂—N[(C₂H₅OH)(CH₃)].
 5. A compound according to claim 1 in theform of a salt.
 6. (canceled)
 7. A method of treatment ofIgE-synthesis-mediated diseases, autoimmune diseases, gastrointestinaldiseases and chronic rejection of transplants which method comprisesadministering a therapeutically effective amount of a compound of claim1 to a subject in need of such treatment.
 8. (canceled)
 9. Apharmaceutical composition comprising a compound of claim 1 inassociation with at least one pharmaceutical excipient.
 10. (canceled)